A Review - Capsule Shell Material From Gelatin to Non Animal Origin

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Review Article

Bhavisha Rabadiya, IJPRBS,

Av

A REVIEW: CAPSULE SH

Accepted Date:

20/02/2013

Publish Date:

27/06/2013

Keywords

Gelatin,

Hydroxy propyl methyl

cellulose,

Starch,

Pullulan,

Polyvinyl alcohol

copolymer

Corresponding Author

Mrs. Bhavisha Rabadiya

IJPRBS$%R &'()

013; Volue 2!3"# *2$+1

ailable Online At www.ijprbs.com

LL MATERIAL FROM GELATIN TO NO

MATERIAL

BHAVISHA RABADIYA, PARESH RABADIYA

Abstract

Capsule is most preferable dosae form.

"idely used as capsule shell material for th

Hard elatin capsule and soft elatin caps

animal oriin and cross lin#in property ot

material that meets the dietary and

veetarian patients and also comply "

re$uirement of elatin need to be invented

animal oriin materials are synthesis such

methyl cellulose, starch, polyvinyl alcohol

etc. and evaluate as a capsule shell material

ISS# 22++$-+13

IJPRBS

ANIMAL ORIGIN

!ill no" elatin is

preparation of the

ule , but due to its

er suitable capsule

cultural needs of

ith the reulatory

. Hence various non

as hydroxyl propyl

opolymer, pullulan

.

PAP)R$%R &'()



Review Article ISS# 22++$-+13

Bhavisha Rabadiya, IJPRBS, 2013; Volue 2!3"# *2$+1 IJPRBS

Available Online At www.ijprbs.com

INTRODUCTION

!he "ord %Capsule& derived from the 'atin"orld&capsula&, "hich means a small box or

container. !he "ord occurs in many

scientific disciplines, ranin from anatomy,

as an enclosin membrane, and in botany,

as a descriptive "ord for fruit, to

astrophysics, as a space vehicle.

(n pharmacy, capsule "ord has been used

to describe a lass ampule and also as a

name of protective cap over the stopper of

a bottle of medicine. (n more recent times,

capsule has been used primarily to describe

solid dosae forms, "hich consist of a

container, filled "ith medicinal substance.

!hey can be divided in main t"o

cateories,& hard capsule& )t"o piece* and

%soft capsule&)one piece* accordin to the

presence of lycerol or another plastici+er

"hich ma#e it soft and elastic.

A!"#$"%&' () C"*'+&':

Capsules mas# the taste and odor of

unpleasant drus and can be easily

administered. !hey are attracted in

appearance and shells are physioloically

inert and $uic#ly diested in the

astrointestinal tract. -s compared to

tablets, capsules are slippery "hen moist

and hence, easy to s"allo" "ith a drauht

of "ater, fe"er aduncts are re$uired and

economical. !hey are easy to handle and

carry. !he shells can be opacified )"ith

titanium dioxide* or colored, to ive

protection from liht.

D-'"!"#$"%&' () C"*'+&':

!he drus "hich are hyroscopic absorb

"ater from the capsule shell ma#in it

fraile and hence are inappropriate for

fillin into capsules. !he concentrated

solutions "hich re$uire previous dilution

are unsuitable for capsules because if

administered as such lead to irritation of

the stomach.

C"*'+& ."#+)"$+-#% '$&*':

R" M"$&-"' )( C"*'+&'

!he ra" materials used in the manufacture

of both hard and soft elatin capsules are

similar. Both contain %&"$-#, "$&,

(("#$' and optional materials such as*(&'' "-' "# *&'&!"$-!&'

A GELATIN CAPSULE

Material used for the elatin production are

Bones, bovine hides and s#in )/iure *. -s

noted in 0SP12/3

elatin is a product






obtained by the partial hydrolysis of

collaen derived from the s#in, "hite

connective tissue, and bones of animals.

!he hydrolysis may be cataly+ed by the

addition of stron acid or base. Gelatin

derived from acid4cataly+ed hydrolysis are

referred to as !ype -, and elatin derived

from the base4cataly+ed hydrolysis are

referred to as !ype B. !he main difference

bet"een elatins derived from these t"o

processes is that the elatin derived from

the acid4cataly+ed process typically exhibits

an isoelectric point )p(* of about 546.

7hereas the p( of elatin obtained from the

base4cataly+ed process is typically 8.519.8.

!he lo"er p( resultin from the treatment

"ith base is due to the hydrolysis of the

amide roups of Glutamine and asparaine,

creatin lutamic acid and aspartic acid.

Because of the manufacturin process used,

elatin molecules exhibit sini:cant

polydispersity; !he molecular "eiht of

individual molecules typically ranes from

9,<<< to 39<,<<<.

!he approximate amino acid composition of

elatin)/iure3* is lycine 3=, Proline 3=,

hydroxyproline 3=, lutamic acid <=,

alanine 6=, arinine >=, aspartic acid ?=,

lysine 8=, serine 8=, leucine @=, valine 3=,

phenylalanine 3=, threonine 3=, (soleucine

=, hydroxylysine =, methionine and

histidine A= and tyrosine A<.9=. !hese

values vary, especially the minor

constituents, dependin on the source of

the ra" material and processin techni$ue@.

Bloom strenth is a measure of the ability

of a iven "eiht of elatin to set up in

"ater under controlled conditions and is a

function of the molecular "eiht of the

elatin molecules, the concentration of the

elatin in the el, and the pH of the el. (t is

a measure of the resultant el&s resistance

to compression and is reported in bloom4

rams or simply rams. Bloom strenth

increases "hen the elatin concentration in

the el increases, "hen the averae

molecular "eiht of the elatin increases,

and "hen the pH of the el approaches

neutrality )from either direction*. Bloom

strenth also can have an effect on the

clarity and color of the li$uid4:lled capsules.

Gelatin "ith bloom strenths ranin from

9< to @<< is available most elatins used in

the manufacture of li$uid4:lled capsules

have bloom strenth of approximately 9<1

3<< for soft els and 33<13>< for hard els.

Gelatin manufacturers commonly blend






different sublots of elatin to meet bloom

re$uirements3.

- schematic presentation of the elatin

manufacturin process appears in the

fiure. 8.

1 H" %&"$-# "*'+&:

!he maority of capsule products is made of

hard elatin capsules. Hard elatin capsulesare made of t"o shells; the capsule body

and a shorter cap. !he cap fits tihtly over

the open end of the capsule body. !he basic

hard elatin capsule shells are made from

mixtures of elatin, suar, and "ater. !hey

are clear, colorless, and essentially

tasteless.

!"o4piece capsules have been used for

almost a century in the pharmaceutical

field, and the elatin has been adopted as

the main material of these capsules due to

its excellent characteristic as a elatini+er.

Ho"ever, elatin is one of the proteins

derived from animals therefore, it is

unstable from a chemical vie"point and has

a ris# of !S.

- perfect hard elatin capsule should have

the follo"in specifications;

• Gel strenth; 3<<1@<< Bloom,

dependin on the elatin type

• Discosity )?<ECF?13@ = "F" in "ater*;

884?< mPa, dependin on the elatin

type

• PH 8.9 4?.9

• -erobic Plate CountA<<<Fram

11

M&$( () *(+$-(# () &.*$4 "

%&"$-# '&':

Some of the maor suppliers of empty

elatin capsules are; li 'illy and Company,

7arner 'ambert&s Capsuel )formerly Par#

avis* and R. P. Scherer Corporation. !he

metal moulds at room temperature aredipped into a hot elatin solution, "hich

els to form a film. !his is dried, cut to

lenth, removed from the mouldsand the

t"o parts are oined toether, these

processes are carried out as a continuous

process in lare machines)/iure9*.

12 S-5& "# '*&-)-"$-(# () "

%&"$-# "*'+&

/or human use, empty capsules ranin in

si+e from <<< the larest to 9 the smallest.

Generally, hard elatin capsule is used to






encapsulate bet"een ?9 m to ram

)/iure?*.

2ote; refer to the ?I reference in the text.

13 S"*& () C"*'+&'

!o prepare capsules easily differentiated

from those of other manufacturers, the

shape of the capsule end )"hich is usually

round* can be altered. Capsules from li'illy )PulvulesJ* have the body shell "ith a

tapered end and the round shaped cap.

Capsules from GlaxoSmithKline have both

ends hihly tapered.

!o ensure reliable closin of the filled

capsules, capsule shells "ith loc#in

rooves )or indentations* have been

prepared .xamples are Posilo#J )Lualicaps,

a division of Shionoi Co., 'td.*, Coni4

SnapJ )Capsuel, a division of Pfi+er, (nc.*,

and 0ni4'oc#J )Cardi4nal Health*. !he t"o

rooves fit into each other for tiht closin

and prevent accidental separation )or

splittin* of the capsules. Capsules from

Capsuel are sold as Snap4/itJ, Coni4SnapJ,

and BcapsJ. Snap4/itJ has the concentric

loc#in rins on the body and cap "hich

prevent reopenin after fillin. !he Coni4

SnapJ capsule, "hich is the improved form

of Snap4/itJ, has the rim of the capsule

body "hich is slihtly tapered )/iure 5*.

!he slihtly tapered body facilitates oinin

on hih speed machines and prevents the

problem of telescopin. !elescopin is

slidin of a capsule body )or a capsule cap*

over another capsule body )or a capsule

cap*. !he tapered rim ma#es it more

difficult to slide a capsule body over

another o"in to the smaller diameter. !he

BcapsJ capsule is different from the Coni4

SnapJ capsule in that the upper capsule

part )cap* covers most of the lo"er part

)body* so that only the rounded ede of the

body is visible. !he decrease in rippin

surface ma#es it impossible to Hard Gelatin

Capsules hold the body and open "ithout

crushin it. !hus, the BcapsJ capsule

provides increased security of the contents

and the interity of the capsule. /iure >

illustrates the differences bet"een ordinary

capsules, Coni4SnapJ capsules, and BcapsJ

capsules)/iure>*.

Some capsules )KapsealJ from Pfi+er, (nc.,

and LualicapsJ from Shionoi Co., 'td.*

are made tamper4proof and lea# proof. !he

oint bet"een the t"o capsule parts are

sealed "ith a elatin or polymer band.

-nother approach has been developed to

ma#e capsules tamper resistant or tamper






evident. !he contact areas of the cap and

body are "etted "ith a mixture of "ater

and ethanol and then thermally bonded at

8<189 EC. -ny attempt to separate a sealed

capsule "ill destroy the capsule5.

1 T4*&' () ."$&-"' )( )--#% -#$( "

%&"$-# "*'+&':

ry solids )Po"ders, pellets, ranules or

tablets*, Semisolids )Suspensions or pastes*,

'i$uids )2on4a$ueous li$uids*.

1 E))&$ () R&"$-!& +.--$4 "#

.(-'$+& (#$&#$ (# '& *(*&$4:

Gelatin is a hyroscopic material, and the

relationships amon relative humidity,

elatin moisture content, and hard elatin

capsule properties are sho"n in /iure 6>.

Bond and 'ees>, Kontny and Muls#i

6 also

have studied the relationship bet"een

relative humidity and brittleness of hard

elatin capsules. Because certain solvents

are #no"n hydrophilic aents, it isparticularly important to monitor the

mechanical properties of li$uid4filled

capsules stored under various conditions of

temperature and relative humidity.

2 S()$ %&"$-# "*'+&:

Soft elatin )also called softel or soft

elastic* capsules consist of one4piece

hermetically sealed soft shells. Soft elatin

capsules are prepared by addin a

plastici+er, such as lycerin or polyhydric

alcohol )e.g., sorbitol*, to elatin. !he

plastici+er ma#es elatin elastic. Soft elatin

capsules come in various shapes such as

spherical, elliptical, oblon, and special tube

shapes "ith and "ithout t"ist off )/iure

*. !hey can contain non4a$ueous li$uids,

suspensions, pasty materials, or dry

po"ders. !hey are especially important to

contain volatile dru substances or dru

materials susceptible to deterioration in the

presence of air.

A!"#$"%&' () '()$ %& "*'+&':

ase of use 4 easy to s"allo", no taste, unit

dose delivery, temper proof, versatile and

accommodates a "ide variety of

compounds filled as a semisolid, li$uid, el

or paste. -vailable in "ide variety of colors,

shapes and si+es. (mmediate or delayed

dru delivery4can be used to improve

bioavailability by deliverin dru in solution

or other absorption enhancin media.

D-'"!"#$"%&' () '()$ %& "*'+&':






Re$uires special manufacturin e$uipment,

stability concerns "ith hihly "ater soluble

compounds, and compounds susceptible to

hydrolysis

- perfect soft capsule elatin should have

the follo"in specifications<

;

• Gel strenth; 9<13<< Bloom,

dependin on the elatin type

• Discosity )?<ECF?13F@ = "F" in "ater*;

3.>18.9 mPa s, dependin on the elatin

type

• 7ell4controlled deree of viscosity

brea#do"n

•

7ell4defined particle si+e to allo" fast

dissolution and deaeration of the

molten mass, even at hih elatin

concentrations

• - broad molecular "eiht distribution

to provide a fast settin and the fusion

temperature bein "ell belo" the

meltin temperature of the plastici+ed

"et film.

!he main elatin types and rades used for

the manufacture of soft capsules are listed

in !able3 toether "ith their

physicochemical specifications. !he proper

choice of the elatin type and rade is

related to technoloical issues, consumer

preference and pricin. /or pharmaceutical

or health and nutrition products, medium

bloom limed bone )'B* elatins, or blends of

limed bone and pis#in )'BFPS* or limed

bone, pis#in and limed hide elatin

)'BF'HFPS* are commonly used, "ith a

certain preference for 'B elatin in the

0nited States and for blended elatins in

urope. 'o"4viscosity, hih4bloom elatins

such as a 3<< Bloom pis#in )PS* or acid

bone )-B*

Gelatin is often used for the encapsulation

of hyroscopic formulations andFor "ater4

sensitive drus, "here standard elatin

formulations have to be modified to contain

less "ater and dry faster, thus improvin

the product stability durin capsule

manufacturin. Mixtures of lo" )A<<

Bloom* and medium Bloom )N9< Bloom*

elatins have been proposed for the

formulation of che"able soft capsules

)Overholt, 3<<* to achieve the desired

mouthfeel and solubility of the shells, a lo"

stic#iness for improved machinability and

sufficient interity for stable fill

encapsulation. (n addition to the






pharmacopoeia rade elatin types listed in

!able 3

.

2ote;Refer to<

reference in the text.

21 F( (..&-" M"#+)"$+& ()

S()$ G&"$-# C"*'+&

• P"$&8P(&'' - "arm sheet of

prepared elatin is laid over the lo"er

plate and the li$uid is poured on it. -second sheet of elatin is carefully put

in place and this is follo"ed by the top

plate of the mold. !he set is placed

under the press "here pressure is

applied to form the capsule "hich is

"ashed off "ith a volatile solvent to

remove any trace of oil from the

exterior3

.

• R($"4 D-& P(&'' !he rotary die

machine is a self4contained unit capable

of continuously automatically

producin finished capsules from a

supply of elatin mass and fillin

material "hich may be any li$uid, semi4

li$uid, or paste that "ill not dissolve

elatin. !"o continuous elatin ribbons,

"hich the machine forms, are brouht

into converence bet"een a pair of

revolvin dies and an eection "ede

)/iure<*3

.

• 2orton Capsule Machine; !his machine

produces capsule completely

automatically by leadin t"o films of

elatin bet"een a set of vertical dies.

!hese dies as they close, open, and

close, are in effect a continual vertical

plate formin ro"s after ro" of poc#ets

across the elatin film. !hese are filled

"ith medicament and as they proress

throuh the dies, are sealed, shaped,

and cut out of the film as capsules

"hich drop into a cooled solvent bath3

.

• -ccoel Capsule Machine. Or Stern

machine; uses a system of rotary dies

but is uni$ue in that it is the only

machine that can successfully fill dry

po"der in a soft elatin capsule3

.

22 S"*& 9 '-5& () "*'+&

Soft elatin capsule is available in various

shapes, si+e and color )/iure* e;

• Spherical 1 <.<9 49 ml

• Ovoid 1 <.<9 4 5 ml

• Cylindrical 1 <.94 39 ml

• !ubes 1 <.9 4 < ml






• Pear shaped 1 <.@ 4 9ml

23 T4*&' () ."$&-"' )( )--#% -#$('()$ %&"$-# "*'+&'

13:

• N&"$ S+'$"#&, &'*&-"4 (-4 -;+-';

e. Cod liver oil capsules

• S(+$-(# F-':

a. -ctive dissolved in a carrier;

Oils such as soybean oil and Milyol >3

)neutral oil, trilycerides of medium chain

fatty acids*

Polyethylene Glycols; especially PG 8<< 4

?<<

Other solvents; -ny other solvent, "hichdoes not derade or solubili+e the elatin

shell, i.e., dimethyl isosorbide, surfactants,

diethylene lycol monoethly ether.

b. Optional (nredients for solution fills;

7ater or alcohol; up to <= "F" )if needed

for solubility*.

Glycerin; to 8= "F" )to retard the

miration of the lycerin out of the shell

into the fill*.

Polyvinylpyrrolidone; 0p to <= "F" used

in combination "ith PG )can increase dru

solubility, and also improve stability by

inhibitin dru crystalli+ation*.

• S+'*&#'-(# F-': -ctive dispersed in a

carrier.

Suspensions can accommodate about @<=

solids before viscosity and fillin become a

problem. Suspensions can be heated up to

@9C to decrease viscosity durin the fillin

process. Suspended solids must be smaller

than >< mesh 44 mill or homoeni+e before

fillin to prevent needles from cloin

durin fillin.

3 S*&-" $4*&' () " %&"$-# "#

'()$ %&"$-# "*'+&'

31 A$&& R&&"'&:

!he rate of release of capsule contents can

be varied accordin to the nature of the

dru and the capsule excipients. (f the dru

is "ater4soluble and a fast release is

desired, the excipients should be

hydrophilic and neutral. (f a slo" release of"ater4soluble dru is desired, hydrophobic

excipients "ill reduce the rate of dru

dissolution. (f the dru is insoluble in "ater,

hydrophilic excipients "ill provide a faster

release hydrophobic and neutral excipients

"ill slo" its release. - very rapid release of






the capsule contents can be obtained by

piercin holes in the capsule to allo" faster

penetration by fluids in the astrointestinal

tract, or by addin a small $uantity of

sodium bicarbonate and citric acid to assist

in openin the capsule by the evolution of

carbon dioxide.

-bout <. to = of sodium lauryl sulfate

may be added to enhance the penetration

of "ater into the capsule and speed

dissolution. (f slo"er release of the active

dru is desired, it can be mixed "ith various

excipients, such as cellulose polymers

)methylcellulose* or sodium alinate. (n

eneral, the rate of release is delayed as the

proportion of polymer or alinate is

increased relative to "ater soluble

inredients, such as lactose. (t should be

mentioned that it is difficult to predict the

exact release profile for a dru and to

obtain consistent results from batch to

batch. /urther, reliable, consistent blood

levels and duration of action can only be

proved "ith controlled bioe$uivalence

studies. (n addition, many medications

exhibit narro" therapeutic indices as the

toxic and therapeutic doses are very close.

!herefore, extemporaneous attempts to

alter release rates to this extent should be

avoided@

.

32 C("$-#% "*'+&':

Coatins have been applied

extemporaneously to enhance appearance

and conceal taste, as "ell as to prevent

release of the medication in the stomach

)enteric coated products*. Most coatins of

capsules re$uire considerable formulation

s#ill and $uality control e$uipment found in

manufacturin facilities. !he capsules can

be coated to delay the release of the active

dru until it reaches a selected portion of

the astrointestinal tract. Materials found

suitable include stearic acid, shellac, casein,

cellulose acetate phthalate and natural and

synthetic "axes the basis of their use is

their acid insolubility but al#aline solubility.

Many of the ne"er coatin materials are

time; erosion4more dependent rather than

acid; base4dependent, i.e. they erode over

time on exposure to astrointestinal

contents rather than over a pH radient.

!here are, in addition, a number of ne"er

materials "ith predictable pH solubility

profiles@

.

321 E#$&-8("$& "*'+&':






nteric4coated capsules resist disinteration

in the stomach but brea# up in the

intestine. !hey have larely been

superseded by enteric4coated tablets. !ypes

of coatin used commercially include

cellulose acetate phthalate and mixtures of

"axes and fatty acids andFor their esters.

nteric coatin may be iven to the

follo"in cateories of drus 1

• /or substances that irritate the astric

mucosa or are destroyed by the astric

uice, and for medicaments, such as

amoebicides and anthelmintics that are

intended to act in the intestine.

• 7hich interfere "ith diestion e..

tannins, silver nitrate and other salts of

heavy metals.

• 7hich are re$uired to produce delayed

action of the dru.

Several coatin methods may be used are

Bea#er4flas# coatin ,ippin , Sprayin@

.

322 S+'$"-#& &&"'& "*'+&';

!he traditional method of ta#in a dose

three or four times a day leads to periods of

excess and deficiency in blood

concentration of the medicament. One "ay

of correctin this and, at the same time,

reducin the number of doses per day, is to

administer a capsule containin numerous

coated pellets that release the dru

successively over a lon period.

!he finely po"dered dru is first converted

into pellets, usually by attachin it to suar

ranules "ith an adhesive. !he pellets are

then treated "ith protective coatins that

delay release of the dru, each batch

receivin a different thic#ness. !he batches

are mixed thorouhly and suitable doses

are filled into capsules. /or example, a

mixture miht contain @< percent of

uncoated pellets, for immediate release of

dru, @< percent each of coated pellets that

release at 8 hours and > hours, and <

percent of neutral pellets, used solely to fill

the capsule. ach batch may be colored

differently to simplify identification and

facilitate control of mixin@

.

33 L-;+- )-& " %&"$-# "*'+&'

(t is enerally accepted that many of today&s

2C&s )2e" Chemical ntities* are poorly

"ater soluble and the classical methods,

such as reduction in particle si+e are no

loner ade$uate to achieve satisfactory

dru adsorption from a solid oral dosae

form. One of the most promisin strateies






to deliver these insoluble compounds is

usin dissolved systems li#e usin lipids,

li$uids or semi4solids to formulate ne"

products. !"p piece hard shell capsules are

one of the most loical approaches "hen

choosin the best dosae form to deliver

these ne" li$uid formulations.

!he ne" technoloy of pac#ain li$uids in

hard elatin capsules is considered a maor

brea#throuh. (t can ma#e a sinificant

contribution to the development of

efficacious pharmaceutical products by

providin the flexibility to rapidly develop

and test in4house formulations "hen only

small $uantities of dru substance is

available. !he process can be scaled4up and

also #ept in4house similar to the operations

of tablettin or po"derFpellet fillin of hard

elatin capsules@

.

A$&#"$-!& ."$&-" )( G&"$-# "*'+&'

!raditionally, elatin has been used almost

exclusively as shell4formin material of soft

capsules. !his is due to its leal status and

its uni$ue physicochemical properties,

namely its oxyen impermeability and the

combination of film formin capability and

thermo reversible solFel formation that

favour its use for the industrial soft capsule

production especially in the rotary die

process. espite these reat advantaes,

elatin has several dra"bac#s that limit its

use for soft capsules;

• !he animal source of elatin can be a

problem for certain consumers such as

veetarians or veans and reliious or

ethnic roups )Qe"s, Muslims, Hindus,

etc.* "ho observe dietary la"s that

forbid the use of certain animal

products.

• Since unmodified elatin is prone to

crosslin#in "hen in contact "ith

aldehydes, solubility problems miht be

expected "ith certain fill formulations.

• !ransparent lo"4colour capsules are

difficult to produce o"in to the effect

of the intrinsic Maillard reaction on

elatin colour.

• !he temperature and moisture

sensitivity of elatin4based soft capsules

is an issue that complicates the use of

soft elatin capsules in very hot and

humid reions and re$uires

• Special pac#ain and storae

conditions to ensure product stability.






• /or lo"4price health and nutrition

products, pricin of commercially

available elatin miht be an additional

problem.

Common causes of cross4lin#in include;

• -ldehydes present in active

pharmaceutical inredients )-P(s*,

excipients, pac#ain materials, or

deradants formed in situ durin

storae

• Hih humidity

• (ndirect catalysis in cross4lin#in

reactions

•

ecomposition of a stabili+er in corn

starch )hexamethylenetetramine*,

"hich forms ammonia and

formaldehyde, "hich in turn promote

cross4lin#in reactions

• Rayon coilers that contain an aldehydic

functional roup8

• Polyethylene lycols that may auto4

oxidi+e to form aldehydes

• 0D liht, especially in the presence of

hih heat and humidity9,?I

• Heat, "hich can cataly+e aldehyde

formation.

!o address these concerns, there has been

a reat interest in the soft capsule industry

in loo#in for elatin substitutes. (ndeed,

several concepts based on synthetic

polymers andFor plant4derived

hydrocolloids have been described in the

patent literature. Ho"ever, only fe" have

ained commercial interest. !his is due to

the fact that a chane in the capsule shell

polymer material re$uires more than ust

overcomin the aforementioned

shortcomins of elatin. (t re$uires both

leal approval and machinability, i.e. either

to mimic most of the physicochemical

elatin characteristics that are important

for rotary die soft capsule production "ith

some adustments of the production

e$uipment for the ne" material

characteristics or to use completely

redesined machinery<

.

B HPMC CAPSULE

!he commercial and neutraceutical mar#ets

have driven the development of alternative

formin materials for traditional capsule

shell material elatin accordin to need.

/ormulator re$uires a non4cross4lin#in






capsule that is "ell characteri+ed,

compatible "ith current excipients and

assays, and has a elatin4li#e dissolution.

Mar#etin prefers a capsule that meets the

dietary and cultural needs of patients.

Manufacturin needs a capsule "ith

elatin4li#e performance that can run on

existin fillin e$uipment. Reulatory "ants

a capsule polymer that has a proven safety

record and "ide reulatory acceptance.

Clinicians need to be certain that patient

compliance is assured.

evelop alternative should provide

improvement in the shell property, physical

strenth, protection from moisture

protection from microbial contamination

protection from liht and oxyen improve

compatibility of fill material "ith capsule

shell.

Several materials have been examined as a

substitute for the elatin in t"o4piece hard

capsules. Hydroxypropylmethyl cellulose

)HPMC* has become a successful alternative

material for t"o4piece capsules and is

actually on the mar#et in the "orld.

Hydroxypropyl methylcellulose )HPMC*,

no" commonly #no"n as hypermellose, is

produced by synthetic modification of the

naturally occurrin polymer cellulose and is

considered safe for normal consumption in

humans5

.

HPMC is "hite to slihtly off "hite po"der

or ranules, hyroscopic after dryin,

practically insoluble in hot "ater, in

acetone, in dehydrated ethanol and in

chloroform, but dissolves in cold "ater

ivin a colloidal solution o"in to the

reversible thermal elation property. HPMC

is available in different substitute type "ith

limits on methoxy and hydroxypropoxy

roups. !hese roups influence many of the

HPMC properties such as elation

temperature, viscosity, flexibility and

hydration>

. HPMC capsules may offer

attractive alternative to elatin capsules

because of elatin and dru

incompatibilities and the strict reulations

reardin the use of animal derived elatin

re$uirin the absence of bovine sponiform

encephalopathy)BS*F transmissible

sponiform encephalopathy)!S* have

encouraed the search for elatin

replacement. Reliious culture and personal

issues may affect patient preference

to"ards the medications presented in

capsule dosae form.HPMC capsule are "ell

suited for moisture sensitive drus, no ris#






of capsule cross4lin#in, excellent for

modified release coatins, flexibility under

extreme storae conditions and

machinability.

HPMC is also bein adopted as a film

coatin or a sustained4release tablet

material in the pharmaceutical field. HPMC

capsules have been developed for both

pharmaceutical products and dietary

supplements. L0-'(4D, developed by

Shionoi Lualicaps, is the first HPMC

capsule developed for eventual use in

pharmaceutical products. L0-'(4D has been

submitted to the /- and its M/ number

is 36<<6

.

HPMC capsules have a lo"er moisture

content specification compared to elatin

capsules. Shionoi Lualicaps Luali4D

capsules contain 84?= and Capsuel Dcaps

contain 945=. HPMC films have less

permeable to "ater vapor and moisture

played a different role to that in elatin

films. (t oes not act as a plastici+er, "hich

means that if the capsules lose their

moisture for "hatever reason, e..

exposure to lo" humidities or are filled "ith

hyroscopic formulations, they do not

become brittle3<

. ried elatin and HPMC

capsules do"n to belo" their standard

moisture content and subected them to a

brittleness test that involved droppin a 9<

"eiht on to them from heiht of < cm.

!he results sho"ed that elatin capsules

belo" about = moisture content become

very brittleness even "hen dried do"n to

belo" =3

.

!he first veetable capsules "ith the

trademar# Deicaps made of HPMC "ere

produced in 6>6 by G.S. !echnoloies

(nc.)no" R.P. Scherer !echnoloies

o"nership*. !he production of HPMC

capsules is by thermal elation and a ellin

system used to lo"er thermal elation

temperature of HPMC33

. !he production

techni$ue remains similar to that of hard

elatin capsules and involves the use of pins

dippin into HPMC solution, althouh the

machinery may re$uire some modification

such as the use of heated pins. !he HPMC

capsules patented are not all the same and

differ mainly in "hether a ellin system is

used and in the type of ellin system.

(nformation reardin the empty HPMC

capsules and their manufacturer is listed in

table 9.

C PVA CAPSULE






(nternational Patent -pplication 7O 6 599

@53@

describes the preferable use of

polyvinyl alcohol )PD-* and optional use of

some other materials, all bein film4formin

polymers that lac# the ellin properties

that are necessary for soft capsule

production usin the conventional rotary

die process. !he invention therefore

provides the use of preformed rolls of

nearly "ater4free plastici+ed films that may

be fed to a rotary die encapsulation unit for

soft capsule production. !o render the film

material more flexible and to assist the

seam formation at temperatures dependin

on the film composition, the films are

partially spray solvated prior to

encapsulation. PD- films accordin to this

invention may be composed of 5<159=

"F" PD-, <19= "F" lycerol and 91<=

"F" starch, "ith a sealin temperature of

8<1><EC, dependin on the deree of

solvation. PD- as an optional elatin

substitute has the advantae of bein less

hyroscopic, thus leadin to soft capsule

shells that are less sensitive to moisture

than soft elatin capsule shells. Moreover,

the capsules are readily "ater soluble "ith

no cross4lin#in tendency. Ho"ever,

prototype capsules lac# the shiny and

smooth surface appearance and the seam

$uality of conventional soft elatin

capsules. (n addition, the reulatory issues

and the formulation of hydrophilic fills are

problems that have to be solved. !o

summari+e, it may be concluded that none

of the elatin4free soft capsule concepts are

fully developed yet. 2evertheless, soft

capsules based on plant4derived or

synthetic polymers are an interestin line

extension to soft elatin capsules "ith the

potential to ain a mar#et share for certain

niche products.

Polyvinyl alcohol )PD-* copolymer capsules

is a form of nonelatin capsule under

development. PD-, acrylic acid )--* and

methyl methacrylate )MM-* are used as

ra" materials. -s previously reported, these

capsules have advantaes, such as lo" as

permeability, and can be particularly

suitable for encapsulation of hydrophilic

solvents, such as polyethylene lycol )PG*

8<<, and surfactants38,39,3?,35,3>I

0sin such

capsules facilitates the formulation of

insoluble drus and is expected to enhance

bioavailability.

PD- copolymer capsules "ere prepared by

the dippin and formin method.






Carraeenan )<.<94<.9=* "as added as a

ellin aent and potassium chloride )<.<94

<.9=* "as added as a ellin promoter. !his

method re$uires no additional investment

for capsule manufacturers because

conventional elatin capsule manufacturin

machines can be used. Prototype PD-

copolymer capsules "ere coloured, sho"ed

a ood loss and "ere not different from

conventional capsules.

!he PD- copolymer capsules displayed the

lo"est level of electrification, as "ell as a

neative chare. !he attenuation of the

surface potential chare of the capsules "as

affected by the functional roups of the ra"

materials and their polymeric structure. !he

PD- copolymer capsules are not easily

electrified and sho" easy attenuation of

any electricity that is enerated.

(n contrast "ith elatin and HPMC capsules,

it has been proven that PD- copolymer

capsules are compatible "ith PG 8<<,

!"een >< and '-BR-SO'38,39,3?I

.

C(.*"-'(# () "*'+& ""$&-'$-

Comparison "ith conventional capsules.

Current commercially available hard

capsules are made of elatin or HPMC.

!able ? lists the advantaes and

disadvantaes of PD- copolymer capsules

compared "ith these capsules. PD-

copolymer capsules have similar advantaes

to HPMC capsules because both have been

developed to overcome the dra"bac#s of

elatin capsules. !he advantaes of PD-

copolymer capsules include no animal4

derived material, a lo" "ater content, no

Maillard reaction and a lo" electrostatic

propensity. -dditionally, PD- copolymer

capsules demonstrate the uni$ue

properties of havin very lo" oxyen

permeability and the ability to contain

macrool 8<<36

.

D STARCH CAPSULE

(t can be formulated "ith conventional

plastici+ers such as lycerol, sorbitol, etc.

)<1?<= "F" of dry shell* and "ater to

form a molten mass that can be extruded to

set "ithin less than 3< s producin

mechanically stron, elastic films on

temperature4 controlled castin drums.

Sealin may be performed at temperatures

bet"een 39 and ><EC, by a fusion process

comparable to the one observed "ith soft

elatin capsules. -fter dryin, mechanically

stron and hihly elastic products can be

achieved.






Prototype capsules "ith lipophilic fill

formulations are shiny "ith hih

appearance stability on storae. !he

capsule shells do not sho" crosslin#in and

exhibit a reater mechanical stability than

soft elatin shells "hen exposed to elevated

humidity and temperature, i.e. even under

hot and humid storae conditions they may

not become stic#y. /ormulation approaches

"ith hydrophilic fills are expected to be as

challenin as for soft elatin capsules.

Oxyen permeability is comparable to

elatin4based shells. !he dissolution

mechanism is completely different to the

one of a soft elatin capsule. On contact

"ith an en+yme4free a$ueous medium at

@5EC, the capsule shell only s"ells, at a rate

and to an extent dependin on the type and

concentration of electrolytes present. !he

capsule content may be released "hen the

shell bursts at its point of lo"est resistance,

i.e. at the seams. 0nder in vivo conditions,

capsule shell dissolution may be induced by

en+ymatic deradation. (nternational Patent

-pplication 7O < @5 >5@<

describes the

formation of soft capsules from a potato

starch )891><= "F"*, "ith a specific

molecular "eiht distribution and

amylopectin content, toether "ith a

conventional plastici+er such as lycerol

)3= "F"*, a lidant and a disinterant.

Soft capsule production may be performed

"ith a rotary die machine "ith nearly

"ater4free formulations that are processed

by hot melt extrusion. - narro" production

"indo" and the use of a hih molecular

"eiht amorphous starch "ith hih

amylopectin content )9<= "F"* are

necessary for the formation of acceptable

capsules. /rom the reulatory point of vie",

starch4based soft capsules are a lo"4price

alternative to soft elatin capsules,

appropriate for pharmaceutical and health

and nutrition products. Moisture sensitivity

and fill compatibility of the capsule shells

are comparable to soft elatin capsules,

"ith the exception that cross4lin#in is not a

problem. Oxyen permeability is expected

to be a little hiher compared to soft elatin

capsules@

.

Shell dissolution re$uires en+ymatic

deradation by amylases on contact "ith

amylase4free a$ueous media at @5EC, the

capsules release their content only by

s"ellin induced disinteration. !he

addition of calcium carbonate is one option

to enhance capsule disinteration further.






!he visual appearance, the seam $uality,

and the lon4term stability of the finished

product of the prototype starch capsules

cannot compete "ith soft elatin capsules.

!his is due to the structural rearranements

"ithin the capsule shells associated "ith

the tendency of starch to retrorade on

storae, in some instances leadin to a

subse$uent plastici+er syneresis@

.

Manufactured by the process of inection

mouldin, starch capsules have been sho"n

to be a very useful alternative delivery

system for orally administered compounds.

Made from potato starch and represent a

direct alternative to hard elatin capsules. (t

Offers advantaes li#e; pH independent

dissolution, suitable for enteric coatin,

tamper evident, produced from non4animal

derived inredients. ifferent si+e capsules

are manufactured )number <, , 3, @,

8*.Officially reconi+ed in 0SP 3@ and 2/ >

!-RG(! technoloy )7est Pharmaceutical

Services* is desined for site4specific

delivery of drus in the astrointestinal )G(*

tract and, in particular, tareted release

into the colonic reion. - #ey area of

application is the delivery of therapeutic

aents for local treatment of lo"er G(

diseases. !he technoloy is based on the

application of pH4sensitive coatins onto

inection4moulded starch capsules@3

.

1 P++"# C"*'+&

Pullulan is a natural "ater4soluble hih

molecular polysaccharide produced from

starch or saccharide by microbial

fermentation. (t has numerous uses as

additives in the food, pharmaceutical and

consumer oods industries. (t is also the

source of dissolvable fiber.

Pullulan capsule is another #ind of

veetable capsule. !he advantaes of

pullulan capsule are as follo"s;

•

'o" oxyen transmission, is about one

eihth of the elatin capsules and one

three hundred of the HPMC capsules. So

pullulan capsules provide enhanced

protection of capsule inredients and

extend shelf life.

• (t has the crystal4clear transparency as

the animal oriin capsule.

• 2o animal protein and fat, no microbial

breedin stable in $uality.



Review Article


Av

• /ree from animal produc

ha+ard of mad co" disea

foot disease etc.

• 2atural veetable oriin,

people "ith different

veetarians

2 NP"*' P++"# C"*'

2PcapsJ a non4animal capsfrom pullulan, a veetable4d

soluble polysaccharide produ

F-%+& 1: F( "$ )( C"*'

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s, no potential

se, mouth and

suitable for all

reliions and

&'

les are madeerived, "ater4

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fermentation proce

capsules are hihly i

transmission, 2Pc

recommended for en

sensitive inredients

protection.Pullulan is

characteri+ed, and

reulatory acceptanc

"ith its proven safety

& ."#+)"$+-#% '$&*'

-$-(# () %&"$-#<=

ISS# 22++$-+13

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s. Because pullulan

permeable to oxyen

ps capsules are

capsulatin oxidation4

to provide enhanced

hihly stable and "ell4

has achieved broad

e around the "orld

record@@

.



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REFERENCE:

.

/ridrun Podc+ec# and Brian ones. %!hehistory of the medicinal capsule& in

Pharmaceutical capsules 3nd

ed. 3<<8;.

3. 0SP @12/ 3?. Roc#ville, M; 0S

Pharmacopeial Convention 3<<>;@6.

@. Stevens, P.D. )663*. 0n#no"n. /ood

-ustralia 88 )5*; @3<1@38.

http;FF""".elatin.co.+aFltn.html.

8. http;FFen."i#ipedia.orF"i#iFGelatin.

9. http;FF""".renineerin.comFreach.ht

ml.

?. 'ippincott 7illiams and "il#ins. %Oral

solid dosae form& in Reminton 1 !he

Science and Practice of Pharmacy, 3th ed,

Dolume 1 ; 63.

5. '- -usburer Hard and soft elatin

capsulesT in Modern Pharmaceutics GS

Ban#er C! Rhodes, ds., Marcel e##er,

(nc.; 2e" Uor#, 2U, 669; @69188<.

>. Bond CM, 'ees K-, Pac#inton Q'.

Cephalexin; a ne" oral broad4spectrum

antibiotic. Pharm Q. 65< 3<9;3<138.

6. Kontny MQ, Muls#i C-. Gelatin capsule

brittleness as a function of relative humidity

at room temperature. (nt Q Pharm. 6>698;561>9.

<. Gabriele Reich, %/ormulation and

physical properties of soft capsules&

available from;

http;FF""".pharmpress.com.

. Overholt, S. M.Che"able soft capsules.

0S Patent ? 39> @><, 3<<.

3. 'ippincott 7illiams and "il#ins. %Oral

solid dosae form& in Reminton 1 !he

Science and Practice of Pharmacy, 3th ed,

Dolume 1 ; 63@.

@. r. Bha"na Bhatt, S.S. -ra"al

Pharmaceutical

!echnoloy%Capsules&,available from;

http;FFnsdl.niscair.res.inFbitstream

8. Sch"ier QR, Coo#e GG, Hartauer KQ, Uu '.

- reactive aldehyde capable of insolubili+in

elatin capsules. Pharm

!echnol.66@5;5>1><.

9. Murthy KS, nders 2-, /a"+i MB.

issolution stability of hard4shell products.

Part (. !he effect of exaerated storae

conditions. Pharm !echnol.6>6@;531>8.






?. Murthy KS, Reisch RG, /a"+i MB.

issolution stability of hard4shell products.

Part ((. !he effect of dissolution test

conditions on in vitro dru release. Pharm.

!echnol. 6>6@;9@19>.

5. raper, P. R., !anner, K. ., Get+, Q. Q.,

Burnett, S. and Uounblood, . /ilm formin

compositions comprisin modified starches

and iota4carraeenan and methods for

manufacturin soft capsules usin same.

(nternational Patent -pplication 7O < <@

?55.666.

>. Robert O. 7illiams (((, Matthe" -.

Sy#ora and Dorapann Mahauna Method to

recover a lipophilic dru from

hydroxypropyl methyl cellulose matrix

tablets. --PS PharmaSci!ech, 3<< 3)3*; >.

6. Shuni 2aata, -dvantaes to HPMC

Capsules; - 2e" Generation&s ru elivery

!echnoloy , 3<<3 3)3*.

3<. Oura, !., /uruya, U. and Matsuura, S.

HPMC capsules 1 -n alternative to elatin.

Pharm. !echnol. ur.,66> <)*;

@3,@8,@?,8<,83.

3. Moa"ia M. -l4!aba#ha, HPMC Capsules;

Current status and future prospects ,ru

development elivery , Capsule

technoloy 3<<33)3*

33. (. Chi"ele, B.. Qones, and /. Pde+ec#.

!he shell dissolution of various empty hard

capsules. Chem Pharm Bull, 3<<< 8>; 694

69?.

3@. Bro"n, M. . (mprovements in or

relatin to encapsulation. (nternational

Patent -pplication 7O 6 5@9 [email protected]?.

38. 2. Hoshi et al., Pharma !ech.

Qapan,3<<@ 6)*; 51@<.

39. 2. Hoshi et al, Pharm. !echnol. ur.,

3<<8 ?)8*; @518?.

3?.

2. Hoshi, -bstracts of 3nd Symposium

on /ormulation !echnoloy )!o#yo, Qapan,

3<<8* B1B3.

27 S. 0ramatsu et al., -bstract of 6th

Symposium on Particulate Preparations and

esins, )Ha#ata, Qapan, 3<<3* ; 88185.

2

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